DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003

PROVISIONAL SPECIFICATION
(Section 10 and rule 13)

TITLE: SUSTAINED RELEASE COMPOSITION OF RUXOLITINIB

Applicant
GLENMARK PHARMACEUTICALS LTD
B/12, Mahalaxmi Chambers,
22, Bhulabhai Desai Road, Mumbai – 400026

The following specification particularly describes the invention and the manner in which it is to be performed.

SUSTAINED RELEASE COMPOSITION OF RUXOLITINIB

FIELD OF THE INVENTION
The present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib, and further relates to a process for preparing such compositions, and a method of use of such compositions in treating one or more disease conditions.

BACKGROUND
Sustained release oral dosage forms, also known as extended-release or controlled-release dosage forms, are pharmaceutical formulations designed to release the active pharmaceutical ingredient (API) over an extended period of time, maintaining therapeutic levels of the drug in the body and minimizing fluctuations in drug concentration. This approach offers several advantages compared to immediate-release formulations, where the drug is released rapidly into the bloodstream.
Ruxolitinib or its water soluble pharmaceutically acceptable salts are marketed as an oral tablet globally for treating various oncological disease conditions. Presently, the oral ruxolitinib tablets are marketed for treating myelofibrosis, polycythemia vera, acute Graft-Versus-Host Disease (GVHD), and chronic GVHD.
The presently approved immediate release oral dosage form containing water soluble salts of ruxolitinib i.e., ruxolitinib phosphate, and it is given to the subject twice daily. There were several adverse events were noticed during clinical studies of immediate release oral ruxolitnib tablets such as thrombocytopenia, anemia, neutropenia and the like.
Further, the immediate release oral ruxolitnib tablets provides pharmacokinetic profile of mean ruxolitinib maximal plasma concentration (Cmax) and AUC increased proportionally over a single dose range of 5 mg to 200 mg (4 times the approved highest recommended total daily dosage of 25 mg twice daily). Mean ruxolitinib Cmax ranged from 205 nM to 7100 nM and AUC ranged from 862 nM*hr to 30700 nM*hr over a single dose range of 5 mg to 200 mg. Oral immediate release tablet is absorbed with 1 hr to 2 hrs post dose, and mean elimination half-life of ruxolitinib is approximately 3 hours and the mean elimination half-life of ruxolitinib and its metabolites is approximately 5.8 hours in healthy volunteers.
The immediate release tablet of ruxolitinib phosphate (marketed name Jakavi® or Jakafi®) provides sharp fall in the plasma concentration of ruxolitinib or its metabolites post 2 hrs from the administration. Hence, immediate release tablet of ruxolitinib phosphate is administered to the subject twice daily.
There were some publications on sustained release tablet of ruxolitinib phosphate.
International Publication No. WO 2014/016396 discloses sustained release formulations of ruxolitinib phosphate comprising various non-erodible materials with pore forming substance(s).
United States Patent No. 10874616 discloses sustained release composition of ruxolitinib phosphate in hydroxylpropyl methyl cellulose (as a matrix forming substance)
United States Patent Application 2023/0172863 discloses sustained release composition of ruxolitinib phosphate comprising polyethylene oxide as release controlling substance.
International Publication No. WO 2023/022520 discloses sustained release composition of ruxolitinib phosphate comprising polyethylene oxide and one or more sustained-release adjuvant.
None of the above published literature discloses non-erodible matrix formulation that are containing one or more release controlling material comprising hydrophobic release controlling material and/or waxes.
The present inventors surprisingly found that a novel sustained release composition for one or more water soluble salt of ruxolitinib comprising one or more release controlling materials that provide patient compliance of reducing number of doses required to achieve a therapeutic effect.

SUMMARY OF THE INVENTION
The present invention relates to a sustained release composition comprising one or more highly water soluble drug(s) or its pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib and a pharmaceutically acceptable release controlling material.
In one embodiment, the present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib and a pharmaceutically acceptable release controlling material; wherein the composition is administered to a subject once daily.
In one embodiment, the present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib and a means for controlling release of ruxolitinib; wherein the composition is administered to a subject once daily.
In some embodiments, the release controlling material is non-swellable in water.
In some embodiments, the release controlling material is hydrophobic substance.
In some embodiments, the pharmaceutical composition of the present invention does not contain pore forming substance. The pore forming substance(s) are channelizing agents and usually water soluble substances.
In some embodiments, the release controlling material is selected from lipids, waxy materials, hydrophobic materials and any combinations thereof.
In some embodiments, the release controlling material is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, hydrogenated castor oil and the likes.
In some embodiments, the release controlling material is free of hydroxypropyl methyl cellulose, and polyethylene oxide.
In some embodiments, the release controlling material is present in the composition from about 2% w/w to about 80% w/w.
In some embodiments, the weight ratio between the water soluble drug to release controlling material is from about 1:0.5 to 1:5.
In some embodiments, the weight ratio between the water soluble drug to release controlling material is selected from 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, and 1:5.
In a specific embodiment, the weight ratio between the water soluble drug to release controlling material is selected from 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, and 1:3.
In an embodiment, the present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib and a pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is selected from ethylcellulose, polyvinyl acetate, poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride), poly (ethyl acrylate-co-methyl methacrylate), cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof of the foregoing.
In an embodiment, the present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib and a pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release composition comprising one or more water soluble salt(s) of ruxolitinib and a pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof, and wherein the composition provides at least about 20% of total amount of ruxolitinib release from said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.lN HCl as dissolution medium and wherein not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.
The present invention provides an oral, sustained release dosage form comprising ruxolitinib, or a pharmaceutically acceptable salt thereof.
The dosage form can contain ruxolitinib, or a pharmaceutically acceptable salt thereof, in an amount of about 10 to about 100 mg, about 20 to about 90 mg, about 25 to about 80 mg, about 30 to about 70 mg, or about 40 to about 60 mg on a free base basis.
In some embodiments, the dosage form contains about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 37.5 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg or about 80 mg on a free base basis. In some embodiments, the dosage form contains about 25 mg of ruxolitinib on a free base basis. In some embodiments, the dosage form contains about 50 mg of ruxolitinib on a free base basis. In some embodiments, the dosage form contains about 55 mg of ruxolitinib on a free base basis.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 10 to about 100 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release composition comprising ruxolitinib phosphate and a pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof, and wherein the composition provides at least about 20% of total amount of ruxolitinib release from said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.lN HCl as dissolution medium and wherein not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.
In some embodiments, the present invention relates to a sustained release composition comprising ruxolitinib phosphate and a pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof, and wherein the composition provides any one or more pharmacokinetic parameter selected from: (i) Ln(Cmax) is in the range from about 200 ng/ml to about 500 ng/ml; (ii) AUC0-12 is in the range of from about 1500 to about 4000; and (iii) AUC0-24 is in the range of from about 2000 to about 5000.

DETAILED DESCRIPTION
In order to describe the present invention, the following definitions are provided. Otherwise all terms are to be accorded their ordinary meaning as they would be construed by one skilled in the relevant art, i.e., drug formulation and therapy.
Definitions:
The term “sustained release” as used herein is defined to mean a substantially gradual rate of release of the ruxolitinib in the once daily sustained release dosage form or the at least one means for controllably releasing the one or more pharmaceutically acceptable water soluble salt(s) of ruxolitinib in a substantially controlled manner per unit time in-vivo. The term “sustained release” is used synonymously with extended release and/or controlled release.
“Sustained-release dosage forms” or dosage forms which exhibit a “sustained-release” of the ruxolitinib as used herein is defined to mean dosage forms administered once daily that provide a release of the water soluble salt(s) of ruxolitinib sufficient to provide a therapeutic dose after administration, and then a gradual release over an extended period of time such that the sustained-release dosage form provides therapeutic benefit over a 24-hour period. The sustained release dosage form alternatively referred as sustained release tablet and/or sustained release capsule.
The rate of release of the ruxolitinib is optimized by features of the dosage form and/or in combination with physiologic or environmental conditions rather than by physiologic or environmental conditions alone. The once daily sustained-release dosage form or the at least one means for controllably releasing the water soluble salt(s) of ruxolitinib of the invention will desirably be contrasted to immediate-release dosage forms, which typically produce large maximum/minimum plasma drug concentrations (Cmax/Cmin) due to rapid absorption of the drug into the body i.e., in-vivo, relative to the drug's therapeutic index i.e., the ratio of the maximum drug concentration needed to produce and maintain a desirable pharmacological response. In immediate-release dosage forms, the drug content is released into the gastrointestinal tract within a short period of time, and plasma drug levels peak shortly after dosing. The design of immediate-release dosage forms is generally based on getting the fastest possible rate of drug release, and therefore absorbed, often at the risk of creating undesirable dose related side effects. The controlled-release dosage forms of the invention, on the other hand, improve the therapeutic value of the active drug by reducing the ratio of the maximum/minimum plasma drug concentration (Cmax/Cmin) while maintaining drug plasma levels within the therapeutic window. The once daily controlled-release dosage form or the at least one means for controllably releasing the ruxolitinib of the invention attempt to deliver therapeutically effective amount of ruxolitinib at constant effective levels to provide therapeutic benefit over about a 24-hour period. The once daily controlled-release dosage form or the at least one means for controllably releasing the ruxolitinib of the invention, therefore, avoid large peak-to-trough fluctuations normally seen with immediate-release dosage forms and provide a substantially flat serum concentration curve throughout the therapeutic period.
The term “Pharmacokinetic parameter(s)” as used herein refers to one or more parameters that are measured by administering a sustained release composition to a subject that they are healthy volunteers. Typically, the pharmacokinetic parameters herein referred are Cmax, AUC and the likes.
The term “subject” as used herein refers to human subject or an animal including mammals (such as monkeys, guinea pig, domestic pets, for instance cats and dogs).
As used herein, the term “about” when used to refer to weight % in a composition or other numeral amounts means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value.
The term “matrix” as used herein refers to a core of the dosage form that provides sustained release of the active agent that is embedded/ dispersed therein. The matrix as used herein preferably does not contains hydroxylpropyl methyl cellulose and/or polyethylene oxide. The term “matrix” is preferably referred as non-erodible release controlling material which is different from erodible release controlling material. The non-erodible release controlling material(s) release active via diffusion mechanism whereas erodible release controlling material(s) release active via swelling, erosion and disintegration mechanism.
The term “means for controlling release of ruxolitinib” as used herein refers to a hydrophobic release controlling material which is optimized to provide release rate not less than 20% of total amount of ruxolitinib in 2 hrs as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.l N HCl as dissolution medium.
The sustained release composition of the present invention comprises (i) a matrix core comprising (a) one or more water soluble salt(s) of ruxolitinib and (b) a means for controlling release of ruxolitinib; (ii) one or more pharmaceutically acceptable excipient(s); wherein the means for controlling release of ruxolitinib comprises one or more agent selected from lipids, waxy materials and/or hydrophobic materials.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 10 to about 100 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 20 to about 80 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 30 to about 60 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 25 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 50 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
In an embodiment, the present invention relates to a sustained release dosage form comprising ruxolitinib of about 55 mg on a free base basis and pharmaceutically acceptable release controlling material; wherein the pharmaceutically acceptable release controlling material is glyceryl behenate, glyceryl dibehenate, waxes, carnauba wax, hydrogenated castor oil and any combinations thereof.
The sustained release composition of the present invention comprises (i) a matrix core comprising (a) one or more water soluble salt(s) of ruxolitinib of about 50 mg to 60 mg, and (b) a means for controlling release of ruxolitinib; (ii) one or more pharmaceutically acceptable excipient(s); wherein the means for controlling release of ruxolitinib comprises one or more agent selected from hydrophilic, lipids, waxy materials and/or hydrophobic materials.
In some embodiment, the matrix core of the sustained release composition comprises materials which are able to provide modified release properties, preferably due to their limited solubility, more preferably due to their limited solubility in aqueous conditions, such embodiments are selected from lipids, waxy materials and/or hydrophobic materials. Examples of hydrophobic material are ethylcellulose, methacrylate copolymer, polyamide, polyethylene, cellulose acetate butyrate, cellulose acetate propionate, and polyvinyl acetate; examples of lipid materials are carnauba wax, cetyl alcohol, hydrogenated vegetable oils, microcrystalline waxes, glyceryl behenate, glyceryl dibehenate, monoglycerides, triglycerides and PEG monostearate; examples for hydrophilic materials are alginates, carbopol, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, xanthan gum and polyethylene oxide.
The sustained release composition of the present invention comprises (i) a matrix core comprising (a) one or more water soluble salt(s) of ruxolitinib of about 55 mg, and (b) a means for controlling release of ruxolitinib; (ii) one or more pharmaceutically acceptable excipient(s); wherein the means for controlling release of ruxolitinib comprises one or more agent selected from ethylcellulose, methacrylate copolymer, polyamide, polyethylene, and polyvinyl acetate, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, microcrystalline waxes, monoglycerides, triglycerides and PEG monostearate, alginates, carbopol, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, xanthan gum and polyethylene oxide.
In some embodiment, the matrix core of the sustained release composition comprises additionally one or more hydrophilic agent(s). The hydrophilic agent(s) includes dibasic calcium phosphate, polyvinylpyrrolidone. carboxyalkylcelluloses, polydextrose, saccharides, and saccharides, such as pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose, and sorbitol.
In some embodiments, sustained release composition of the present invention comprises (i) intragranular portion comprising: a matrix core comprising (a) one or more water soluble salt(s) of ruxolitinib and (b) a means for controlling release of ruxolitinib; (ii) extragranular portion comprising: one or more pharmaceutically acceptable excipient(s); wherein the means for controlling release of ruxolitinib comprises one or more agent selected from lipids, waxy materials and/or hydrophobic materials.
In some embodiment, the matrix core is combination of a means for controlling release of ruxolitinib and one or more pharmaceutically acceptable excipients.
The one or more pharmaceutically acceptable excipient(s) is selected from, but not limited to, diluent, disintegrant, pore forming substance, binder, lubricant, glidant, coating materials and any combinations of the any of the foregoing.
The sustained release composition of present invention comprises one or more release controlling material selected from stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil), hydrogenated soybean oil and hydrogenated soybean oil & castor wax) stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate, glyceryl monostearate, stearic acid, glycerylbehenate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and mixtures thereof.
Examples of lipids useful for the manufacture of the once daily controlled-release dosage form comprising a lipid dosage form or at least one means for controllably releasing the ruxolitinib, wherein the at least one means comprises a lipid matrix core will desirably include, for example, glyceryl monostearate, mixtures of glyceryl monostearate and glyceryl monopalmitate, glycerylmonooleate, a mixture of mono, di and tri-glycerides, glycerylmonolaurate, long chain carboxylic acids, long chain carboxylic acid esters, long chain carboxylic acid alcohols, and mixtures thereof. The long chain carboxylic acids will desirably contain from 6 to 30 carbon atoms; in certain embodiments at least 12 carbon atoms, and in other embodiments from 12 to 22 carbon atoms. In some embodiments this carbon chain is fully saturated and unbranched, while others comprise one or more double bonds. In at least one embodiment the long chain carboxylic acids contain 3-carbon rings or hydroxyl groups. Examples of saturated straight chain acids include n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefinic straight chain monocarboxylic acids. Non-limiting examples of these include oleic acid, gadoleic acid and erucic acid. Also useful are unsaturated (polyolefinic) straight chain monocaboxyic acids, examples of which include linoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid. Examples of long chain carboxylic acid esters include glyceryl monostearates; glyceryl monopalmitates; mixtures of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate glyceryl monooleate and glyceryl monolinoleate; glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate; acetylated glycerides such as distilled acetylated monoglycerides; glyceryl behenate; mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide; mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide; d-alpha tocopherol polyethylene glycol 1000 succinate; mixtures of mono- and diglyceride esters such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and di-glycerides; lactated mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and propylene glycol; lactylic esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids, propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of waxes; cetearyl octanoate; C10-30 cholesterol/lavosterol esters; sucrose long chain carboxylic acid esters; transesterified ethoxylated vegetable oil; polyethoxylated unsaturated fatty acid triglycerides; glyceryl palmitostearate; or mixtures thereof. The amount of the at least one lipid will desirably range from about 2% to about 80%, such as for example, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80% of the total weight of the composition.
Examples of waxes that will desirably be used for the manufacture of the once daily controlled-release dosage form comprising a wax dosage form or at least one means for controllably releasing the water soluble salt(s) of ruxolitinib, wherein the at least one means comprises a wax matrix core will desirably include, for example, a natural or synthetic wax or oil, for example hydrogenated fats such as hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, normal waxes, insect and animal waxes, such as for example, chinese insect wax, beeswax, spermaceti, fats and wool wax; vegetable waxes, such as for example, bamboo leaf wax, candelilla wax, carnauba wax, Japan wax, ouricury wax, Jojoba wax, bayberry wax, Douglas-Fir wax, cotton wax, cranberry wax, cape berry wax, rice-bran wax, castor wax, Indian corn wax, hydrogenated vegetable oils (e.g., castor, palm, cottonseed, soybean), sorghum grain wax, Spanish moss wax, sugarcane wax, caranda wax, bleached wax, Esparto wax, flax wax, Madagascar wax, orange peel wax, shellac wax, sisal hemp wax and rice wax; mineral waxes, such as for example, Montan wax, peat waxes, petroleum wax, petroleum ceresin, ozokerite wax, microcrystalline wax and paraffins; synthetic waxes, such as for example, polyethylene wax, Fischer-Tropsch wax, chemically modified hydrocarbon waxes, cetyl esters wax, paraffin, or glyceryl monostearate, and suitably has a melting point of from 35 to 140° C., fatty alcohols, fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), higher aliphatic (e.g., C10-20) acids, alcohols, long chain fatty acids, and mixtures thereof. Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1:5,000 (w/w). The aliphatic alcohol will desirably be lauryl alcohol, myristyl alcohol or stearyl alcohol, cetyl alcohol, cetostearyl alcohol, or any combination thereof. The amount of the at least one wax will desirably range from about 2% to about 80%, such as for example, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80% of the matrix core dry weight.
Example of diluent(s) that may be used in the composition of the present subject matter include, but not limited to, lactose monohydrate, lactose anhydrous, microcrystalline cellulose, starch, dextrose, dextrin, mannitol, maltodextrin, isomalt, sorbitol, sucrose, dextrates, powdered cellulose, pregelatinized starch, di- and tri-basic calcium phosphate and combinations thereof.
In some embodiments, the diluent comprises microcrystalline cellulose, or, lactose monohydrate or both. In some embodiments, said diluent can be present in the compositions in an amount of 5 to about 80% by weight, based on the total weight of the composition. In some embodiments, said diluent can be present in an amount of about 40 to about 80%, about 40 to about 75%, or about 45 to about 70% by weight, based on the total weight of the composition. In some embodiments, said fillers can be present in an amount of about 40%, about 45%, about 50%, about 55%, about 60% or about 65%, based on the total weight of the composition.
Example of disintegrant(s) that may be used in the composition of the present subject matter are known in the art and may include, but not limited to, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidones such as crospovidone, polacrilin potassium, calcium silicate sodium starch glycolate, cross-linked PVP, alginic acid, croscarmellose sodium and combinations thereof. In some embodiments the disintegrant may comprise sodium starch glycolate or croscamellose sodium, or both. In one embodiment, the disintegrant is croscarmellose sodium. In some embodiments, the amount of disintegrant(s) present in the composition may be about 1% to about 40%, or about 1 to about 30%, or about 1 to about 20%, or about 1 to about 15%, or about 1 to about 10%, or about 1 to about 8%, or about 1 to about 5%, or about 3% to about 7%, or about 4 to about 6%, based on the total weight of the composition. In some embodiments the amount of disintegrant may be about 1% or about 2% or about 3% or about 4% or about 5% or about 6% or about 7% or about 8% or about 9% or about 10% or about 11% or about 12% or about 13% or about 14% or about 15% based on total weight of composition.
Example of lubricant(s) that may be used in the composition of the present subject matter are known in the art and may include but not limited to, magnesium stearate, calcium stearate, stearic acid, myristic acid, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine, sodium stearyl fumarate and combinations thereof. In some embodiments, the lubricants comprise magnesium stearate, stearic acid or both. In some embodiments, amount of lubricant(s) present in the composition may be from about 0.2 to about 5%, or from about 0.2 to about 4%, or from about 0.2 to about 3%, or from about 0.2 to about 2%, based on the total weight of the composition. In some embodiments, the amount of lubricant may be about 0.2% or about 0.3% or about 0.4% or about 0.5% or about 0.6% or about 0.7% or about 0.8% or about 0.9% or about 1% or about 1.1% or about 1.2%, or about 1.3%, or about 1.4% or about 1.5% or about 1.6% or about 1.7% or about 1.8% or about 1.9% or about 2% or about 3% or about 4%, based on the total weight of the composition.
Example of glidant(s) that may be used in the composition of the present subject matter include, but not limited to colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, sodium stearyl fumarate and mixtures thereof. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the amount of glidant(s) present in the composition may be from about 0.2 to about 10%, or from about 0.2 to about 8%, or from about 0.2 to about 5%, or from about 0.2 to about 4%, or from about 0.2 to about 3%, or from about 0.2 to about 2%, based on the total weight of the composition.
Example of binder(s) that may be used in the composition of the present subject matter are known in the art and include, but not limited to, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose copovidone, acacia, alginate, alginic acid, candelilla wax, carnuba wax, liquid glucose, sucrose, tragacanth, polyethylene glycol, polyvinyl alcohol, polymethacrylates, corn starch, erythrosine sodium, gelatin, glyceryl monostearate, sodium carboxymethyl cellulose and povidone. In some aspects, the binder is copovidone, povidone, pregelatinized starch, and combinations thereof. In some further aspects, the binder is copovidone. The amount of binder(s) present in the composition may be from about 1 to about 10%, or from about 2 to about 8%, or from about 3 to about 7%, or from about 4 to about 6%, based on the total weight of the composition. In some embodiments the amount of binder may be about 3% or about 4% or about 5% or about 6%, based on the total weight of the composition.
Example of coating material(s) in the composition of the present subject matter can be present in an amount of 0 to about 5% by weight, based on the total weight of the composition. Non-limiting illustrative examples of film-coating agents include hypromellose or polyvinyl alcohol based coating with titanium dioxide, talc and optionally colorants available in several commercially available complete coating systems. The film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to color the formulation, or to modify or control the release of the active pharmaceutical ingredient from the formulation.
In some embodiments of the present invention, the hydrophobic dosage form or hydrophobic matrix core is comprised of at least one hydrophobic polymer, which will desirably range from about 2% to about 80%, such as for example, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70% of the matrix core dry weight.
In some embodiments of the present invention, the hydrophobic dosage form or hydrophobic matrix core is comprised of at least one hydrophobic polymer, which will desirably range from about 2% to about 80%, such as for example, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70% of the total weight of the composition.
Examples of hydrophobic polymers that will desirably be used for the manufacture of the once daily controlled-release dosage form comprising a hydrophobic dosage form or at least one means for controllably releasing the water soluble salt(s) of ruxolitinib, wherein the at least one means comprises a hydrophobic polymer matrix core will desirably include, for example, one or more alkylcelluloses, such as for example, C1-6 alkyl cellulose (e.g., ethylcellulose) and one or more C12-36 aliphatic alcohols, a pharmaceutically acceptable acrylic polymer, such as for example, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), or glycidyl methacrylate copolymers.
The release of water soluble salt(s) of ruxolitinib from the hydrophobic dosage forms or the at least one means for controllably releasing the ruxolitinib, wherein the at least one means comprises at least one hydrophobic matrix core will desirably be adjusted to the desired rate, by the addition of one or more release-modifying agents into the hydrophobic dosage form or hydrophobic matrix core.
In some embodiments, the pharmaceutical composition of the present invention does not contain pore forming substance. The pore forming substance(s) are channelizing agents and usually water soluble substances.
In some embodiments, the pharmaceutical composition of the present invention comprises one or more water soluble salt(s) of ruxolitinib and a pharmaceutically acceptable release controlling material; wherein the composition provides dissolution not less than 20% of total amount of ruxolitinib is released from said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.l N HCl as dissolution medium and wherein not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.
In some embodiments, the weight ratio between the water soluble drug to release controlling material is from about 1:0.5 to 1:5.
In some embodiments, the weight ratio between the water soluble drug to release controlling material is selected from 1:0.5, 1:1, 1.1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, and 1:5.
In a specific embodiment, the weight ratio between the water soluble drug to release controlling material is selected from 1:0.5, 1:1, 1.1.5, 1:2, 1:2.5, and 1:3.
In an embodiment, the sustained release composition of the present invention is osmotic pump delivery mechanism.
In some embodiments, the sustained release composition of the present invention does not contain any immediate release portion.
In some embodiments, the means for controlling release of ruxolitinib includes osmotic subcoat.
The semipermeable membrane comprises at least one pharmaceutically acceptable excipient, at least one polymer, wax, or combination thereof, although appropriately treated inorganic materials such as ceramics, metals or glasses will desirably be used. When the semipermeable membrane comprises at least one polymer, the molecular weight of the at least one polymer or combination of polymers should be such that the polymer or combination of polymers is solid at the temperature of use i.e., both in-vitro and in-vivo.
In some specific embodiments of the present invention as follow:
A sustained release composition comprising: i) one or more water soluble salt(s) of ruxolitinib and ii) a pharmaceutically acceptable release controlling material; wherein the release controlling material is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, hydrogenated castor oil and any combinations of any foregoing.
A sustained release composition comprising: i) one or more water soluble salt(s) of ruxolitinib and ii) a pharmaceutically acceptable release controlling material; wherein the release controlling material is one or more hydrophobic substance(s) and the sustained release composition is bioequivalent to twice a day administration of corresponding dose of commercially available immediate release formulation of ruxolitinib, at least on the basis of exposure (AUC).
A sustained release composition comprising: i) one or more water soluble salt(s) of ruxolitinib in the range of from about 5% w/w to about 70% w/w, ii) a pharmaceutically acceptable release controlling material in the range of from about 2% w/w to about 80% w/w; wherein the release controlling material is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, hydrogenated castor oil and any combinations of any foregoing.
A sustained release composition comprising: i) one or more water soluble salt(s) of ruxolitinib in the range of from about 5% w/w to about 70% w/w, ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w; and iii) one or more a pharmaceutically acceptable excipient(s) selected from diluent, disintegrant, pore forming substance, binder, lubricant, glidant, coating materials and any combinations thereof; wherein the release controlling material is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, and hydrogenated castor oil.
A sustained release composition comprising: i) one or more water soluble salt(s) of ruxolitinib in the range of from about 5% w/w to about 70% w/w, ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w; iii) one or more diluent(s) selected from lactose, microcrystalline cellulose, starch, dextrose, dextrin, mannitol, maltodextrin, isomalt, sorbitol, sucrose, dextrates, sugar spheres, xylitol, fructose, lactitol, maltitol, erythritol, maltose, raffinose, polydextrose, trehalose, calcium carbonate, calcium sulphate, dibasic calcium phosphate, chitin, chitosan, kaolin, ethylcellulose, magnesium carbonate, magnesium oxide, sodium bicarbonate, sodium carbonate, powdered cellulose, pregelatinized starch, di- and tri-basic calcium phosphate and any combinations of the any of the foregoing; and iv) one or more a pharmaceutically acceptable excipient(s) thereof.
A sustained release composition comprising: a) an intragranular materials comprises: i) one or more water soluble salt(s) of ruxolitinib; ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w, and the release controlling agent(s) is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, and hydrogenated castor oil; and iii) a diluent in the range of from about 5% w/w to about 98% w/w and the diluent is selected from lactose, microcrystalline cellulose, starch, dextrose, lactitol, maltitol, mannitol, dibasic calcium phosphate, calcium carbonate, powdered cellulose, and pregelatinized starch; and b) an extragranular material comprises one or more pharmaceutically acceptable excipient(s).
A sustained release composition comprising: a) an intragranular materials comprises: i) one or more water soluble salt(s) of ruxolitinib; ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w, and the release controlling agent(s) is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, and hydrogenated castor oil; and iii) a diluent in the range of from about 5% w/w to about 98% w/w and the diluent is selected from lactose, microcrystalline cellulose, starch, dextrose, lactitol, maltitol, mannitol, dibasic calcium phosphate, calcium carbonate, powdered cellulose, and pregelatinized starch; and b) an extragranular material comprises one or more pharmaceutically acceptable excipient(s); wherein the composition provides at least about 20% of total amount of ruxolitinib release from said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.lN HCl as dissolution medium and wherein not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.
An once-daily sustained release composition comprising: a) an intragranular materials comprises: i) one or more water soluble salt(s) of ruxolitinib; ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w, and the release controlling agent(s) is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, and hydrogenated castor oil; and iii) a diluent in the range of from about 5% w/w to about 98% w/w and the diluent is selected from lactose, microcrystalline cellulose, starch, dextrose, lactitol, maltitol, mannitol, dibasic calcium phosphate, calcium carbonate, powdered cellulose, and pregelatinized starch; and b) an extragranular material comprises one or more pharmaceutically acceptable excipient(s); wherein the composition provides at least about 20% of total amount of ruxolitinib release from said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.lN HCl as dissolution medium and wherein not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.
An once-daily sustained release composition comprising: a) an intragranular materials comprises: i) one or more water soluble salt(s) of ruxolitinib; ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w, and the release controlling agent(s) is selected from carnauba wax, and hydrogenated castor oil; and iii) a diluent in the range of from about 5% w/w to about 98% w/w and the diluent is selected from lactose, microcrystalline cellulose, starch, mannitol, dibasic calcium phosphate, calcium carbonate, powdered cellulose, and pregelatinized starch; and b) an extragranular material comprises one or more pharmaceutically acceptable excipient(s); wherein the composition provides at least about 20% of total amount of ruxolitinib release from said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.lN HCl as dissolution medium and wherein not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.
An once-daily sustained release composition comprising: a) an intragranular materials comprises: i) one or more water soluble salt(s) of ruxolitinib; ii) one or more release controlling material in the range of from about 2% w/w to about 80% w/w, and the release controlling agent(s) is selected from glyceryl dibehenate; and iii) a diluent in the range of from about 5% w/w to about 98% w/w and the diluent is selected from lactose, microcrystalline cellulose, starch, mannitol, dibasic calcium phosphate, calcium carbonate, powdered cellulose, and pregelatinized starch; and b) an extragranular material comprises one or more pharmaceutically acceptable excipient(s); wherein the composition provides any one or more pharmacokinetic parameter selected from: (i) Ln(Cmax) is in the range from about 200 ng/ml to about 500 ng/ml; (ii) AUC0-12 is in the range of from about 1500 to about 4000; and (iii) AUC0-24 is in the range of from about 2000 to about 5000.
A sustained release pharmaceutical composition comprising ruxolitinib or pharmaceutical acceptable salts thereof and a means for controlling release of ruxolitinib; wherein the means for controlling release of ruxolitinib comprises one or more hydrophobic substance(s) comprising one or more wax, one or more lipid and one or more water insoluble polymers and wherein the composition is suitable for once daily administration.
A sustained release pharmaceutical composition comprising: a) an intragranular materials comprises: ruxolitinib or pharmaceutical acceptable salts thereof; one or more hydrophobic substance(s) is in the range of about 5% w/w to about 40% w/w, and wherein one or more hydrophobic substance(s) is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, and hydrogenated castor oil.
In an embodiment, the present invention relates to a process for preparing sustained release composition comprising ruxolitinib; the process comprises following steps: (i) preparing intragranular portion comprising a water soluble salt of ruxolitinib, one or more release controlling material; (ii) preparing extragranular portion comprising one or more pharmaceutically acceptable excipients; and (iii) lubrication.
The process for preparing intragranular or extragranular portion is selected from wet granulation, dry granulation, direct compression, co-milling, roller compaction or any combinations thereof.

EXAMPLES
Example-1: Sustained release table composition of Ruxolitinib phosphate
Ingredients Formulation
1 2 3 4 5 6
Intragranular % w/w
Ruxolitinib Phosphate 16.1 16.1 16.1 16.1 16.1 14.67
Anhydrous Dibasic Calcium Phosphate 42.9 19.5 19.5 19.5 19.5 17.78
Lactose Monohydrate NA 44.6 25.1 25.1 24.4 39.11
Glyceryl dibehenate 20.5 15.4 15.4 5.4 10.2 15.56
Extragranular
Microcrystalline cellulose - - - - - 6.67
Colloidal Silicon Dioxide 3.9 2.0 2.0 2.0 2.0 0.89
Lactose Monohydrate NA NA 19.5 29.6 24.6 0
Lubrication
Magnesium Stearate 1.5 1.5 1.5 2.0 2.0 2.67
Stearic Acid 0.5 1.0 1.0 1.2 1.2 0.89
Total 100 100 100 100 100 100

Manufacturing process:
Matrix core was manufactured by any of the known methods such as shifting, wet granulation, dry granulation, direct compression, co-milling, and roller compaction and further mixing of intragranular ingredients. Extragranular portion was prepared by shifting, and mixing of ingredients as mentioned above. Blending intragranular portion with extragranular portion for 5-20 minutes, and lubricating the material. Compressing the above blend to a tablet.

Example-2: Dissolution studies of tablet compositions of Example-1
The first dissolution studies were determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 ml 0.1N HCl as dissolution media.
Examples Formulation 3 Formulation 4 Formulation 6
Hydrophobic release controlling material (% w/w) 15.4 5.4 15.56
30 mins 22 28 --
1 Hr (60 min) 31 61 30
2 Hr (120 min) 44 80 45
4 Hr (240 min) 61 94 48
6 Hr (360 min) 74 99
8 Hr (480 min) 84 99 54
10 Hr (600 min) 93 99
12 Hr (720 min) 99 99 58
16 Hr (960 min) 102 96 61

The second dissolution studies were determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 ml Phosphate Buffer pH 6.8 as dissolution media.
Examples Formulation 3 Formulation 4 Formulation 5 Formulation 6
Hydrophobic release controlling material (% w/w) 15.4 5.4 10.2 15.56
30 mins 2 - - -
1 Hr (60 min) 4 - - 43
2 Hr (120 min) 6 75 62 46
4 Hr (240 min) 7 85 84 48
5 Hr (300 min) - - - 53
6 Hr (360 min) 10 88 89
7 Hr (420 min) - - - 58
8 Hr (480 min) 12 89 92
9 Hr (540 min) - - - 64
10 Hr (600 min) 10 - -
11 Hr (660 min) - - - 70
12 Hr (720 min) 13 90 94
15 Hr (900 min) - - - 85
16 Hr (960 min) 14 90 94 -

Example-3: Dissolution study of Formulation 6 in different time points and after different storage conditions
Dissolution
Media 900 mL 0.1N HCl/ USP-II/50 RPM
Condition Initial 1M
(40°C/75% RH) 1M
(25°C/60% RH) 3M
(25°C/60% RH) 3M
(40°C/75% RH)
0.5Hr 20 17 19 19 17
1Hr 29 25 27 31 25
2Hr 42 37 39 52 38
4Hr 60 55 56 67 62
6Hr 74 - 79 87
8Hr 85 82 79 90 101
10Hr 95 - - 98 102
12 Hr 102 97 95 100 102

Conclusion: The formulation 6 with glyceryl behenate as a release controlling agent provided expected dissolution profile over different time points in different storage condition.
Example-4: Sustained release tablet formulation of Ruxolitinib
Ingredients Formulation 7
% w/w
Ruxolitinib Phosphate 14.7
Anhydrous Dibasic Calcium Phosphate 17.8
Lactose Monohydrate 39.1
Glyceryl dibehenate 15.6
Polyvinyl pyrrolidone 1.8
Extra granular
Microcrystalline Cellulose 6.7
Colloidal Silicon Dioxide 0.9
Magnesium Stearate 2.7
Stearic Acid 0.9
Total weight 100

Example-5: Sustained release tablet formulation of ruxolitinib with carnauba wax and hydrogenated castor oil as release controlling agent
Ingredients Formulation 8 Formulation 9 Formulation 10 Formulation 11
% w/w
Ruxolitinib Phosphate 14.67 14.67 14.67 14.67
Anhydrous Dibasic Calcium Phosphate 10.00 10.00 14.89 14.89
Lactose Monohydrate 40.00 33.33 26.67 40.00
Hydrogenated castor oil 30.00 30.00 0 0
Carnauba Wax 0 0 30.00 25.11
Polyvinyl pyrrolidone 0 0 1.78 0.00
Extra granular
Microcrystalline Cellulose 0 6.67 6.67 0
Colloidal Silicon Dioxide 1.78 1.78 1.78 1.78
Magnesium Stearate 2.67 2.67 2.67 2.67
Stearic Acid 0.89 0.89 0.89 0.89
Total weight 100 100 100 100

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other 5 arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:We Claim:
1. A sustained release pharmaceutical composition comprising ruxolitinib or pharmaceutical acceptable salts thereof and a means for controlling release of ruxolitinib; wherein the means for controlling release of ruxolitinib comprises one or more hydrophobic substance(s) comprising one or more wax, one or more lipid and one or more water insoluble polymers and wherein the composition is suitable for once daily administration.
2. The sustained release pharmaceutical composition as claimed in claim 1, wherein pharmaceutical acceptable salt of ruxolitinib is ruxolitinib phosphate.
3. The sustained release pharmaceutical composition as claimed in claim 1, wherein ruxolitinib is present in an amount of about 5% w/w to about 70% w/w as free base with respect to the total weight of the composition.
4. The sustained release pharmaceutical composition as claimed in claim 1, wherein one or more hydrophobic substance(s) is selected from the group consisting of ethylcellulose, polyvinyl acetate, poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride) (Eudragit® RS, Eudragit® RL), poly (ethyl acrylate-co-methyl methacrylate) (Eudragit® NE), cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, glyceryl behenate, glyceryl dibehenate, carnauba wax, hydrogenated castor oil and combinations thereof.
5. The sustained release pharmaceutical composition as claimed in claim 4, wherein the hydrophobic substance is present in an amount of about 5% w/w to about 30% w/w with respect to the total weight of the composition.
6. The sustained release pharmaceutical composition as claimed in claim 1, wherein the composition is matrix tablet.
7. The sustained release pharmaceutical composition as claimed in claim 1, wherein the sustained release composition comprises
(i) intragranular portion comprising: a matrix core comprising:
(a) ruxolitinib or pharmaceutical acceptable salts thereof and
(b) a means for controlling release of ruxolitinib;
(ii) extragranular portion comprising: one or more pharmaceutically acceptable excipient(s);
wherein the means for controlling release of ruxolitinib is selected from one or more wax, one or more lipid and one or more water insoluble polymers.
8. The sustained release pharmaceutical composition as claimed in claim 7, wherein the means for controlling release of ruxolitinib or pharmaceutical acceptable salts thereof comprises one or more hydrophobic substance(s) selected form glyceryl dibehenate, glyceryl behenate, carnauba wax, hydrogenated castor oil.
9. A sustained release pharmaceutical composition comprising: an intragranular materials comprises:
(i) ruxolitinib or pharmaceutical acceptable salts thereof;
(ii) one or more hydrophobic substance(s) is in the range of about 5% w/w to about 40% w/w, and wherein one or more hydrophobic substance(s) is selected from glyceryl dibehenate, glyceryl behenate, carnauba wax, and hydrogenated castor oil.
10. The sustained release pharmaceutical composition as claimed in claim 9, wherein the pharmaceutical composition releases at least about 20% of total amount of ruxolitinib from the said composition within 2 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 500 mL of 0.lN HCl as dissolution medium and not more than 70% of total amount of ruxolitinib is released from said composition within 4 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 mL of re-buffered dissolution medium to pH 6.8.

Dated this 4th day of September 2024.

Signature: -------------------------------
Dr. Mahalaxmi Andheria
Vice President – IPM